UC Riverside

The peripheral endocannabinoid (eCB) system is a key determinant of energy homeostasis in various biological tissues. Studies indicate eCB dysregulation in multiple peripheral organs, including the small intestine and adipose tissue, is strongly associated with diet-induced obesity (DIO). Moreover, elevated levels of peripheral endogenous cannabinoids can perpetuate the obesity phenotype by promoting appetite. To assess the impact of intestinal eCB activity on food intake, these studies first examined the role of cannabinoid type-1 receptor (CB1) in modulating dietary preferences. The CB1 receptor, a key component of the ECS, has been extensively studied for its involvement in the modulation of appetite, adipogenesis, and adipokine secretion. Cannabinoid-mediated influence on appetite is well-established with certain exogenous cannabinoids found in Cannabis sativa, such as Δ9-tetrahydrocannabinol (THC), which stimulates appetite by activating the eCB system. Paradoxically, however, recent evidence from retrospective human observational studies reports lower prevalence of obesity and decreased incidence of diabetes in cannabis users compared to non-users. It remains unclear if cannabinoids like THC are responsible for any metabolic improvements associated with long-term cannabis use. Thus, these studies also assessed the impact of chronic cannabinoid exposure on the development of DIO. By utilizing ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS), we compare the metabolic outcomes of chronic exposure to pure THC versus whole cannabis extract with dose-matched THC content. Furthermore, we examined the role of adipocyte CB1 in regulating energy homeostasis within adipose tissue in response to chronic cannabinoid exposure¬¬¬ in vivo and in vitro. Collectively, these studies use a combination of genetic and pharmacological tools to understand the role of peripheral CB1 in facilitating shifts in energy homeostasis. Findings from these studies indicate a substantial role for intestinal CB1 in modulating food intake and dietary preference. This body of work also provides novel insight into the role of adipocyte CB1 in mitigating the differential metabolic improvements following chronic cannabinoid exposure.